Scientific background:

Summary: The gene codes the calcium sensing receptor excerting its funtion in renal tubules and the parathyroid gland. Hypocalciuric hypercalcemia ensues in heterozygous individuals, and two affected alleles cause neonatal hyperparathyroidism.

Gene: The gene of the calcium sensing receptor (CASR) is about 103 kb in size. It is localized on chromosome 3 (3q13.3-q21). There are two splice variants. Both consists of 7 exons but they have different first exon and promoter. Both promoters contain a vitamin D reseponse element (VDRE) the binding site of the vitamin D receptor. Translation starts in second exon. This way both splice variants don't differ in there amino acid content.

Pathology: This extracellular sensing calcium receptor is a G-protein-coupled glycoprotein that contains seven membrane spanning helical structures, an extracellular domain and an intracellular carboxyterminal tail. The receptor has amino acid sequence similarity with cerebral metabotropic glutamate receptor (GRM2) and both receptors might have there origin in bacterial nutrient binding proteins. The calcium sensing receptor can be found in parathyroid gland, thyroid C cells and along all the tubules of the nephron. It does not contain one of the well known height-affinity calcium binding motifs. It seems that large negatively charged parts of the extracellular domain of the receptor can bind several divalent ions and hereby modulate the receptor response over the whole range of physiological calcium concentrations.

Clinical signs: The loss of function mutations in this gene result in familial hypercalcemic hypocalciuria (FHH) or in severe neonatal hyperparathyroidism (NSHPT). In contrast to FHH where PTH secretion shows a reduced sensitivity to extracellular calcium concentration where in NSHPT there is absolutly no response. Compared to plasma calcium we find an inadequitly hight PTH level an a reduced renal clearance of calcium and magnesium. Hypocalciuria remains after parathyroidectomy. Only loop diuretics can increase calcium excretion. On the other hand gain of function mutations is described leading to autosomal dominant hypocalcemia characterized by significantly low PTH levels.

Epidemiology: Only few families with such disorders are described. Patients with less severe symptoms might be more often in patients with hypertension, osteoporosis or enuresis.

Interpretation: The detected of a relevant mutation in the gene can confirm the diagnosis and help in family consulting.

Test strategy: The indication for this therapy exists in cases with severe disorders of calcium homeostasis where symptoms are conform with one of the types of mutations in this gene. Consequences for medical services should exit.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Hebert SC et al. (1997) Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis.
Canaff L et al. (2002) Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D.